Continuing to develop the technique of imaging cells in three-dimensional long-term histocultures of mammalian tissues, we have applied both standard and newly developed methods to the study of cell-cell interaction inside stratified rat lingual epithelium and to the invasion of normal tissue by melanoma cells in vitro. By using confocal microscopy in combination with histocultures of stratified rat lingual epithelium we have proved the existence of gap junctions between cells of one stratum as well as between strata. Neural cells PC12 differentiate in blocks of stratified epithelia without additional growth factors. The neurites formed by PC-12 cells establish contacts with epithelia. Imaging of genetic variants of mouse melanoma cells implanted into histocultured mouse lung showed that the pattern of invasion correlates with the activity of metalloproteinase on the surface of the invading cell. The overproduction of the protease inhibitor on the surface of melanoma cells results in dissemination of single cells through the normal tissue. This pattern of invasion correlates with the decrease of cell-cell adhesion in cell suspension. These systems provide the opportunity to study the mechanisms of normal and pathological cell-cell interactions in a native-state microenvironment as well to test various drugs affecting these interactions.